EP1150671B1

EP1150671B1 - Use of pyrethroid compounds to promote hair growth

Info

Publication number: EP1150671B1
Application number: EP99965013A
Authority: EP
Inventors: Toshihiko Seki; Seishiro Fujii; G. Paolo Dotto
Original assignee: General Hospital Corp
Current assignee: General Hospital Corp
Priority date: 1998-11-20
Filing date: 1999-11-19
Publication date: 2007-02-28
Anticipated expiration: 2019-11-19
Also published as: DE69935350T2; EP1150671A4; JP2002530332A; US20010027213A1; US6288112B1; EP1150671A1; WO2000030636A1; DE69935350D1

Description

Background of the Invention

Unwanted hair loss can plague both men and women of all ages. It can arise as the result of a variety of underlying causes, including hormonal imbalance, genetic predisposition and exposure to toxic substances. Alopecia areata is a non-scarring inflammatory hair loss disease that can affect men, women, and even children. The factors that activate the onset of alopecia and the mechanisms of its development are not well understood. It is characterized clinically by the sudden appearance of a round or oval patch of non-scarring and painless hair loss with spontaneous remissions and exacerbations (Weitzer, Am. Fam. Physician 41(4) :1197-1201 (1990)). The annual incidence of alopecia areata is approximately 2 per 10,000 population. 5% to 10% of patients, especially children, result in a total loss of all of the scalp hair (alopecia totalis). Although the disease itself is non-life threatening, the cosmetic and psychological impact on both patients and parents is tremendous. Patients usually suffer from a higher than normal rate of major depression and/or other anxiety disorder (Colon et al., Comprehensive Psychiatry 32 (3) : 245-251 (1991); Beard, J. Am. Acad. Dermatol. 14(4) : 697-700 (1986)).
RU 2004154 and RU 2028802 disclose the use of compositions containing the type II pyrethroid cypermethrin to treat insect infestation of sheep. These documents do not disclose the use of pyrethroids for promoting hair growth.
FR 2659014 discloses a lotion for treatment of hair loss that includes a crude extract of the pyrethrum plant, along with other components of vegetable, mineral, and animal origin.
Naturstoffchemie (Nuhn, 1990) discloses that synthetic pyrethroids are chemically more stable than the active substances in the pyrethrum plant, natural pyrethrums.

Summary of the Invention

In general, the invention features use of a type II pyrethroid selected from the group comprising cypermethrin, deltamethrin, or fenvalerate for the preparation of a composition for promoting hair growth, including for the treatment of a human with an insufficient amount of hair or an insufficient rate of hair growth. In a preferred embodiment, the pyrethroid is administered topically. The pyrethroid can be administered to the scalp, face, chest, legs, and other regions of the body. In a preferred embodiment, the pyrethroid is provided in a composition, e.g., a pharmaceutically acceptable composition. In a preferred embodiment, the weight percent of the pyrethroid ranges from 0.005% to 5%; the weight percent of the pyrethroid ranges from 0.01% to 2%. In a preferred embodiment, the compound is administered at any point in a hair cycle, e.g., in the anagen (growth) phase of hair growth; in the telogen (resting) phase of hair growth; in the catagen (the period between the telogen phase and the anagen phase) phase of hair growth.
A subject in need of hair growth promoting treatment may be identified; after administration of a pyrethroid compound, the effect of the administration on hair growth may be evaluated; the treatment can involve more than one administration, e.g., at least two, three, or four administrations, of the pyrethroid compound.
In a preferred embodiment, the subject can be male or female that suffers from genetic pattern baldness; suffers from a hormonal disorder which decreases hair growth; has received a treatment, e.g., radiation, or chemotherapy, or a drug which inhibits hair growth; or has had a surgical procedure, e.g., skin graft, which is in need of hair growth.
In another aspect, the invention features the use of a compound of the formula:
wherein R¹ is
in which each of R^a, R^b, R^c, and R^d, independently, is H, fluoro, chloro, bromo, iodo, or C_1-4 alkyl. Alkyl can be either a straight or branched group. Some examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. R² is CN or C≡CH; and R³ is
in which X is O, S, NH, or CH₂; and each of R' and R", independently, is H, fluoro, chloro, bromo, iodo, or C_1-4 alkyl. for the preparation of a composition for promoting hair growth. The compound can exist as a salt, e.g., a hydrochloride salt. There can be more than one substituents on each aromatic ring, e.g., more than one R^d, R', or R" on each ring.
In a preferred embodiment, the compound is administered topically. The compound can be administered to the scalp, face, chest, legs, and other regions of the body. In a preferred embodiment, the compound is provided in a composition, e.g., a pharmaceutically acceptable composition. In a preferred embodiment, the compound is administered at any point in a hair cycle, e.g., in the anagen (growth) phase of hair growth; in the telogen (resting) phase of hair growth; in the catagen (the period between the telogen phase and the anagen phase) phase of hair growth.
In a preferred embodiment, R² is CN. In a preferred embodiment, R¹ is
in which each of R^a, R^b and R^c, independently, is H, fluoro, chloro, bromo, iodo, or C_1-4 alkyl. In a preferred embodiment, each of R^a and R^b, independently, is chloro or bromo; and R^c is H. In a preferred embodiment, each of R^a and R^b, independently, is chloro; X is O; and each of R' and R", independently, is H. In a preferred embodiment, each of R^a and R^b, independently, is bromo; X is O; and each of R' and R", independently, is H. In a preferred embodiment, R¹ is
in which R^d is H, fluoro, chloro, bromo, iodo, or C_1-4 alkyl. In a preferred embodiment, R^d is chloro; X is O; and each of R' and R", independently, is H. In a preferred embodiment, X is O; each of R' and R", independently, is H.
A subject in need of hair growth promoting treatment may be identified; after administration of the compound, the effect of the administration on hair growth may be evaluated; the treatment can involve more than one administration, e.g., at least two, three, or four administrations, of the compound.
In a preferred embodiment, the subject can be male or female that suffers from genetic pattern baldness; suffers from a hormonal disorder which decreases hair growth; has received a treatment, e.g., radiation, or chemotherapy, or a drug which inhibits hair growth; or has had a surgical procedure, e.g., skin graft, which is in need of hair growth.
A composition for promoting hair growth includes the type II pyrethroid cypermethrin, deltamethrin, or fenvalerate, and a pharmaceutically acceptable carrier. In a preferred embodiment, the composition is sterile. In a preferred embodiment, the composition includes a fragrance. In a preferred embodiment, the weight percent of the pyrethroid in the composition ranges from 0.005% to 5%; the weight percent of the compound in the composition ranges from 0.01% to 2%. In a preferred embodiment, the compound is administered at any point in a hair cycle, e.g., in the anagen (growth) phase of hair growth; in the telogen (resting) phase of hair growth; in the catagen (the period between the telogen phase and the anagen phase) phase of hair growth.
A kit for promoting hair growth includes, a compound described herein and instruction for use of the compound to promote hair growth.
A container which includes a compound described herein, has one or more of the following properties: it contains less than 5.0, 1.0, 0.5, or 0.1 g of the compound described herein; it is air tight; it is waterproof; or in addition to the compound described herein, it contains a fragrance or other cosmetic ingredient.
By promoting hair growth is meant an increase in the total mass of hair or the total length of the hairs, in a unit area, e.g., per cm², as compared to nontreated tissue. It can include one or more of: an increase in the length or growth rate of a hair shaft, an increase in the number of hairs, or an increase in the thickness of a hair. In a preferred embodiment, the growth rate is increased.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative.
Other features or advantages of the present invention will be apparent from the following detailed description of several embodiments, and also from the appending claims.

Detailed Description

The invention relates to the use of specific pyrethroid Type II compounds, i.e., cypermethrin, deltamethrin or fenvalerate for the preparation of a composition for promoting hair growth. Type I pyrethroid compounds (e.g., permethrin) differ from type II pyrethroid compounds (e.g., cypermethrin) in that type II compounds possess a cyano group on the α-carbon atom of the phenoxybenzyl moiety.
Another aspect of this invention features the use of a composition having a compound of formula (I) as an active ingredient for the preparation of a composition for promoting hair growth.
wherein R¹ is
in which each of R^a, R^b, R^c, and R^d, independently, is H, fluoro, chloro, bromo, iodo, or C_1-4 alkyl; R² is CN or C≡CH; and R³ is
in which X is O, S, NH, or CH₂; and each of R' and R", independently, is H, fluoro, chloro, bromo, iodo, or C_1-4 alkyl. The compounds described above exhibit geometrical and optical isomerism. For example, geometrical isomerism can result from the configuration of different substituents on the cyclopropyl ring with respect to one another and the ring. Optical isomerism can arise from different arrangement of the substituents on the carbon atom attaching to the α-cyano or the α-ethynyl group. Both optically active and racemic mixtures of pyrethroid compounds (or their salts) can be employed in the composition of this invention.
The compounds described above can be synthesized according to procedures known in the art, e.g., by transesterification or Wittig reaction. A detailed description of the preparation of the pyrethroid compounds can be found in U.S. Patent No. 4,024,1ε3.
A pharmaceutical composition containing a compound described herein can be used to promote hair growth. The compositions can be used to treat alopecia (including androgenic alopecia, e.g., male pattern baldness, and alopecia areata). The use of such a composition for the manufacture of a medicament for promoting hair growth is also within the scope of this invention.
Hair growth may be promoted by administering to a subject an effective amount of a compound described herein.
An effective amount of the composition of the present invention is defined as the amount of the composition which, upon administration to an animal in need, confers a hair growth-promoting effect on treated animals. The effective amount to be administered to an animal is typically based on a variety of factors including age, sex, surface area, weight, and conditions of the animal. Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, New York, 1970, 537. An effective amount of a compound described herein in the composition of this invention, i.e., doses, e.g., daily doses, can range from 0.01 mg/kg to 25 mg/kg; from 0.1 mg/kg to 12.5 mg/kg. Effective doses will also vary, as recognized by those skilled in the art, dependant on route of administration, excipient usage, and the possibility of co-usage with other treatments such as usage of other hair growth-promoting compounds.
The pharmaceutical composition may be administered via the parenteral route, including orally, topically, subcutaneously, intraperitoneally, intramuscularly, intranasally, and intravenously. Topical administration is preferred. Repeated administration of the composition, e.g., repeated topical administration, can be used. More than one route of administration can be used simultaneously, e.g., topical administration in association with oral administration. Examples of parenteral dosage forms include aqueous solutions of the active agent, in a isotonic saline, 5% glucose or other well-known pharmaceutically acceptable excipient. Solubilizing agents such as cyclodextrins, or other solubilizing agents well-known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the hair growth-promoting composition.
The composition of this invention can also be formulated into dosage forms for other routes of administration utilizing conventional methods. A pharmaceutical composition can be formulated, for example, in dosage forms for oral administration in a capsule, a tablet (each including timed release and sustained release formulations), or a gel seal. Capsules may comprise any standard pharmaceutically acceptable material such as gelatin or cellulose derivatives. Tablets may be formulated in accordance with the conventional procedure by compressing mixtures of pyrethroid compounds and a solid carrier, and a lubricant. Examples of solid carriers include starch and sugar bentonite. The hair growth-promoting composition can also be administered in a form of a hard shell tablet or capsule containing, for example, lactose or mannitol as a binder and a conventional filler and a tableting agent.
Topical administration of the hair growth-promoting compounds described herein presents an attractive route of administration amongst the many different routes described above. Such topical pharmaceutical compositions can exist in many forms, e.g., in the form of a solution, cream, ointment, gel, lotion, shampoo, or aerosol formulation adapted for application to the skin. The weight percent of the active ingredient in the composition, i.e., the pyrethroid compound, can be useful in promoting hair growth in ranges from 0.01% to 5% (based on the total weight of the composition) in admixture with a pharmaceutically acceptable carrier. A wide variety of carrier materials can be employed in the hair growth-promoting composition of this invention such as alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oils, and polyethylene glycols. Other additives, e.g., fragrance or other cosmetic ingredients, can be present in the composition.
The following specific examples, which describe the hair growth-compositions of this invention and biological testings of such compositions, are to be construed as illustrative.

Example 1

The following example was performed to determine if pyrethroid compounds cause skin irritation (as indicated by ear thickness in mice). Skin irritants may contribute to promoting hair growth.
Prior to the experiment, ear thickness of mice (C3H strain, female, 16 weeks of age, n = 3/group) was measured with a thickness gage (Mitsutoyo Corp.). After measuring ear thickness of both ears, 10 µL of ethanol was applied on left ear and 10 µL of a pyrethroid solution (1% pyrethroid compound in ethanol) was applied to the right ear. Ear thickness was measured for three consecutive days after administration. The results of left and right ear thickness are tabulated in Table 1 below: Table 1

Left Ear

day 0 1 2 3

Group I

Ethanol only (x 0.01mm) 27.7 27.7 27.3 27.7

SD 0.58 0.58 0.58 1.15

Group II

Ethanol only (x 0.01mm) 27.0 27.3 27.3 27.7

SD 0 0.58 0.58 0.58

Group III

Ethanol only (x 0.01mm) 27.3 28.3 27.7 27.3

SD 0 1.15 1.15 0.58

Group IV

Ethanol only (x 0.01mm) 27.3 27.7 27.3 28.0

SD 0.58 0.58 0.58 1.00

Right Ear

day 0 1 2 3

Group I

Cypermethrin (x 0.01mm) 27.7 27.7 27.3 28.0

SD 0.58 0.58 0.58 1.00

Group II

Deltamethrin (x 0.01mm) 27.0 27.3 27.3 28.0

SD 0 0.58 0.58 1.00

Group III

Fenvalerate (x 0.01mm) 27.3 28.0 28.0 27.0

SD 0.58 1.00 1.73 1.00

Group IV

Permethrin (x 0.01mm) 27.3 27.7 27.7 28.3

SD 0.58 0.58 0.58 1.15
As can be seen from Table 1 above, the pyrethroid-containing compositions, i.e., the compositions containing cypermethrin, deltamethrin, fenvalerate, or permethrin did not increase ear thickness when compared to ethanol. In other words, all four compositions tested did not have primary irritancy at a concentration of 1% in ethanol.

Example 2

Another ear thickness experiment was performed. Ear thickness of mice (Sencar strain, female, 10 weeks of age, n = 3/group) was measured with a thickness gage (Mitsutoyo Corp.). After measuring the thickness of both ears at the beginning of the experiment, 20 µL of 12-O-tetradecanoyl-phorbol 13-acetate (TPA) at a concentration of 10^-4 M in acetone was applied on both ears, followed by the application of 10 µL of ethanol on the left ears and 10 µL of the four compositions tested in Example 1 on the right ears (at a concentration of 1% of pyrethroid compound in ethanol solution). Again, ear thickness was monitored over three consecutive days following administration of the compositions. The results are provide in Table 2. Table 2

Left Ear

day 0 1 2 3

Group I

Ethanol only (x 0.01mm) 24.0 27.7 28.3 28.3

SD 1.00 28.0 2.52 1.53

Group II

Ethanol only (x 0.01mm) 26.0 28.0 29.0 29.0

SD 2.65 0.58 2.00 1.73

Group III

Ethanol only (x 0.01mm) 24.0 27.3 29.0 28.3

SD 0 1.53 1.00 0.58

Group IV

Ethanol only (x 0.01mm) 23.7 29.7 27.7 28.0

SD 0.58 3.06 2.08 1.73

Right Ear

day 0 1 2 3

Group I

Cypermethrin (x 0.01mm) 24.0 26.7 28.3 27.3

SD 1.00 0.58 2.31 0.58

Group II

Deltamethrin (x 0.01mm) 26.0 27.3 29.0 28.0

SD 2.65 0.58 2.00 1.73

Group III

Fenvalerate (x 0.01mm) 24.0 26.3 26.7 26.7

SD 1.00 0.58 0.58 0.58

Group IV

Permethrin (x 0.01mm) 23.3 27.3 27.0 27.7

SD 0.58 1.53 0 0.58
As was seen in Example 1, the compositions tested failed to cause skin irritation, as compared to ethanol.

Example 3

This experiment was conducted to test the skin irritancy of the compositions of this invention on hair-growing areas of test subjects, i.e., female mice (10 weeks old) of the C3H strain (n = 5/group). After clipping the hair of the back skin of mice with an electric clipper, 5 µL/cm² of each four composition tested in Examples 1 and 2 (at a concentration of 1% in an ethanol solution) were applied. The application was administered once a day, for 3 consecutive days. Skin irritation was evaluated by unaided visual inspection at the end of the third day. The level of irritation was scored as follows:

-: no irritation
±: weak irritation
+: clear irritation
++: strong irritation

The results are presented in Table 3. Table 3

Concentration after 72 hours

Group I

Cypermethrin 1% in ethanol -

Group II

Deltamethrin 1% in ethanol -

Group III

Fenvalerate 1% in ethanol -

Group IV

Permethrin 1% in ethanol -
Based on the results in Table 3, the four compositions, i.e., the compositions containing cypermethrin, deltamethrin, fenvalerate, and permethrin, all failed to cause skin irritation (redness) with three repeated topical administration to mice skin at a concentration of 1% in ethanol.

Example 4

The ability of topical administration of pyrethroid compounds to promote hair growth was assessed in female C3H strain mice (10 weeks old; n = 5/group). Hair on the back skin of the mice was clipped carefully with an electric clipper. 5 µL/cm² of the five compositions tested in the examples above were applied to the mice daily. The level of hair growth at the applied skin areas were evaluated by unaided visual inspection at the indicated time. Cyclosporin A was used as a control. The results are shown in Table 4. Table 4

Day 7 14 19 29 36

Group I

Cypermethrin 1% 0 0 2 4 5

Ethanol 0 0 0 0 0

Group II

Deltamethrin 1% 0 0 1 5 5

Ethanol 0 0 0 0 0

Group III

Fenvalerate 1% 0 0 1 4 4

Ethanol 0 0 0 0 0

Group IV

Permethrin 1% 0 0 0 0 0

Ethanol 0 0 0 0 0

Cyclosporin A 1% 0 5 5 5 5

Ethanol 0 0 0 0 0
The results showed that the compositions containing cypermethrin, deltamethrin, and fenvalerate were effective in promoting hair growth. New hair growth occurred at areas of the skin where the compositions were applied.

Example 5

The experiment described in Example 4 was repeated with a commercially available hair growth-promoting compound (5% minoxidil) as a control. The results are shown in Table 5. Table 5

Week 1 2 3 4 5 6

Group I

Cypermethrin 1% 0 0 5 5 5 5

0.1% 0 0 5 5 5 5

0.01% 0 0 0 0 0 0

Ethanol 0 0 0 0 0 0

Group II

Deltamethrin 1% 0 2 5 5 5 5

0.1% 0 0 5 5 5 5

0.01% 0 0 1 1 1 3

Ethanol 0 0 0 0 1 1

Group III

Fenvalerate 1% 0 0* 3* 5 5 5

0.1% 0 0 5 5 5 5

0.01% 0 0 0 0 0 0

Ethanol 0 0 0 0 0 0

Group IV

Permethrin 1% 0 0 0 0 0 1

0.1% 0 0 0 0 0 0

0.01% 0 0 0 0 0 0

Ethanol 0 0 0 0 0 0

Minoxidil 5% 0 0 2 3 4 4

Ethanol 0 0 0 0 0 0

* skin color of 2 out of 5 mice was lightened; no hair growth was observed at the indicated time period
The results above showed that the three compositions containing cypermethrin, deltamethrin, and fenvalerate were effective in promoting hair growth at concentrations of 0.1% and 1% in ethanol solutions. New hair growth occurred at areas of the skin where the compositions were applied. Moreover, the hair growth potency was dose dependent.

Other Embodiments

From the above description, one skilled in the art can ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. For example, the hair growth-promoting compositions of the invention can contain two or more pyrethroid compounds.

Claims

Use of a type II pyrethroid selected from cypermethrin, deltamethrin, or fenvalerate for the preparation of a composition for promoting hair growth.
The use of claim 1, wherein the composition is to be administered topically.
The use of claim 1 or 2, wherein the composition is sterile.
The use of claim 3, wherein the weight percent of the pyrethroid in the composition ranges from 0.005% to 5%.
The use of claim 4, wherein the weight percent of the pyrethroid in the composition ranges from 0.01 % to 2%.
Use of a compound of the formula:
wherein
R¹ is
in which each of R^a, R^b, R^c, and R^d, independently, is H, fluoro, chloro, bromo, iodo, or C_1-4 alkyl;
R² is CN or C≡CH, and
R³ is
in which X is O, S, NH, or CH₂; and each of R' and R", independently, is H, fluoro, chloro, bromo, iodo, or C_1-4 alkyl;
or a salt thereof for the preparation of a composition for promoting hair growth.
The use of claim 6, wherein said composition is to be administered topically.
The use of claim 6 or 7, wherein said composition is sterile.
The use of claim 6, wherein R² is CN.
The use of claim 9 wherein R¹ is
in which each of R^a, R^b and R^c, independently, is H, fluoro, chloro, bromo, iodo, or C_1-4 alkyl.
The use of claim 10, wherein each of R^a and R^b, independently, is chloro or bromo; and R^c is H.
The use of claim 11, wherein each of R^a and R^b, independently, is chloro.
The use of claim 12, wherein X is O; and each of R' and R", independently, is H.
The use of claim 11, wherein each of R^a and R^b, independently, is bromo.
The use of claim 14, wherein X is O; and each of R' and R", independently, is H.
The use of claim 9, wherein R¹ is
in which R^d is H, fluoro, chloro, bromo, iodo, or C_1-4 alkyl.
The use of claim 16, wherein R^d is chloro.
The use of claim 17, wherein X is O; and each of R' and R", independently, is H.
The use of claim 9, wherein X is O.
The use of claim 19, wherein each of R' and R", independently, is H.
The use of any of the preceding claims, wherein the composition further comprises a fragrance.